Organophosphate compounds, in particular organic esters of substituted phosphoric acids, have been developed for use as chemical weapons. These compounds inhibit cholinesterases and disrupt the peripheral nervous system by preventing these enzymes from breaking down acetylcholine. Some organophosphate compounds are sufficiently potent that even brief exposure may be fatal.
Organophosphate anticholinesterase agents include tabun (Ethyl N,N-dimethylphosphoramidocyanidate, also referred to as GA), sarin (O-Isopropyl methylphosphonofluoridate, also referred to as GB), soman (O-Pinacolyl methylphosphonofluoridate, also referred to as GD), and VX (O-ethyl-S-[2(diisopropylamino)ethyl]methylphosphonothiolate). Tabun, sarin, and soman in particular are highly volatile and easily disseminated in vapor form. They are also readily absorbed through the lungs, eyes, skin, and intestinal tract.
Individuals who survive exposure to organophosphate nerve agents may experience morbidity as a result of such exposure. Some survivors of sarin exposure, for example, have exhibited conditions including post traumatic stress syndrome, memory deficits and altered evoked potentials (Murata K, Araki S, Yokoyama K, Okumura T, Ishimatsu S, Takasu N and White R F, Asymptomatic sequelae to acute sarin poisoning in the central and autonomic nervous system 6 months after the Tokyo subway attack, J Neurol 244: 601-606, 1997). Munitions workers exposed to organophosphate agents in the U.S. demonstrated EEG changes, while a similar population in Russia showed long lasting memory loss, sleep disorders and neurological impairments (Romano J A, McDonough J H Jr, Sheridan R E and Sidell F R. “Health Effects of Low-Level Exposure to Nerve Agents,” Chemical Warfare Agents: Toxicity at Low Levels, edited by Somani S M and Romano J A, CRC Press, 2001, pp. 1-24; Duffy F H, Burchfiel J L, Bartels P H, Gaon M and Sim V M, “Long-Term Effects of An Organophosphate Upon the Human Encephalogram,” Toxicology and Applied Pharmacology, 1979, 47: 161-176).
No effective therapies currently exist for treating the long-term effects of exposure to organophosphate agents in individuals who survive such exposure. In addition, the current standard of care for treating acute organophosphate exposure, namely the injection of atropine, carries a risk of adverse reactions. In view of the threat posed by organophosphate agents, improved therapies for treating individuals exposed to such agents and for preventing the harm that these agents can cause are needed.